Parasitic infections are a major worldwide health problem, with a global prevalence of human parasitic infection exceeding 50% and increasing. Parasites are found in four divisions of the animal kingdom, one of which is the Protozoa which include C. parvum, L. donovani, and P. falciparum.
C. parvum is a coccidian protozoan that infects the epithelial cells lining the digestive and respiratory tracts of mammals. The protozoan preferentially invades the epithelial cells lining the microvilli lining the small intestine, but all sites of the gastrointestinal tract (including the esophagus, stomach, colon, common bile duct, gall bladder, liver, rectum, and pancreatic duct) can be involved. The most common clinical manifestations of the resulting infection, commonly called cryptosporidiosis, are characterized by voluminous watery diarrhea, cramping abdominal pain, and weight loss. Nausea, vomiting, fatigue, headache, and myalgia may also be present. In immunocompetent individuals, the infection causes a generally self-limited diarrhea and results in spontaneous eradication of the parasite from the intestinal mucosa and a protective acquired immunity. Severe consequences of cryptosporidiosis, however, can occur in hosts with immature or deficient immune systems. These include young children (usually under five years old), patients undergoing immunosuppressive drug therapy, geriatric hosts having decreased immune responsiveness, and patients with congenital or acquired immunodeficiencies (e.g., Human Immunodeficiency Virus ("HIV") infected and Acquired Immunodeficiency Syndrome ("AIDS") patients). These individuals frequently develop a profuse, protracted diarrheal illness which progresses to a chronic infection of the intestinal epithelium and, potentially, cryptosporidial dissemination into the alveolar and tracheal epithelium.
At least five species of Plasmodium infect humans. Of these, P. falciparum is responsible for the most serious form of malaria. The disease is transmitted by the bite of an infected mosquito which has previously sucked the blood of a person suffering from malaria. The infected individual initially experiences chills for 15 to 60 minutes coincident with the release of a brood of merozoites. This is usually accompanied by headache, nausea, and vomiting, and is succeeded by chills and a febrile stage lasting several hours. The infections may be asymptomatic or may terminate in death. The parasitized red blood cells--especially in the case of falciparum malaria--become sticky and plug up the smaller vessels. The obstructing action has a variety of effects: tissue anoxia and necrosis, bursting of vessels, electrolyte imbalance, etc., affecting many organs.
Human leishmaniasis is caused by protozoal species and subspecies of the genus Leishmania. Nonhuman mammals (e.g., dogs, cats, rodents, horses, sheep, and cattle) are the reservoirs for this infection, which is transmitted to man most often by the bites of infected female sandflies. Four morphologically indistinguishable species infect humans: L. donovani, L. tropica, L. mexicana, and L. braziliensis, producing visceral leishmaniasis, cutaneous leishmaniasis, and mucocutaneous leishmaniasis. In the case of visceral leishmaniasis, the intracellular amastigote form multiplies chiefly in macrophages and produces a disease of various parts of the reticuloendothelial system, causing severe hepatosplenomegaly, along with enlargement of lymph nodes, fever, fatigue, malaise, and secondary infections, and usually is fatal if untreated. The most common clinical manifestations in cases of cutaneous and mucocutaneous leishmaniasis are characterized by formation of ulcers and lesions to the skin and mucous membranes.
Effective and practical antiparasitic vaccines have yet to be devised, and chemotherapy is thus the most efficient and inexpensive single method to control most parasitic infections. Safe and effective drugs are still needed to prevent or treat some major parasitic infections, for example, leishmaniasis, cryptosporidiosis, and malaria.
At present, notwithstanding the fact that more than hundreds of different compounds have been tested, no completely effective treatment for most protozoans in man or animals has been disclosed. Most attempts at conventional chemotherapy with known antiparasitic, antifungal, antibiotic or antiviral agents have been unsuccessful. Other pharmaceuticals, for example, the antimalarials (i.e., chloroquine phosphate, primaquine phosphate, and pyrimethamine sulfadoxine) are losing their utility because of the development of drug resistance. Of greatest concern is the spread of multidrug-resistant strains of P. falciparum, the most dangerous and prevalent plasmodial species. Pharmaceuticals such as amphotericin B and pentamidine isethionate, indicated for treatment of leishmaniasis, have proven unsatisfactory because they cause unacceptable levels of toxicity at therapeutic doses.
Several colostrum preparations have been used to treat some protozoal infections, such as C. parvum, the best results being obtained with hyperimmune bovine colostrum harvested from dairy cows vaccinated with C. parvum antigens. Treatment of protozoal gastrointestinal disorders of parasitic protozoan origin by administration of hyperimmune milk products is disclosed in U.S. Pat. No. 5,106,618 (Apr. 21, 1992) to Beck et al. Despite promising indications, considerable variation has been observed in the therapeutic efficacies of different colostrum preparations. As a result, current treatments center around palliative remedies in addition to treatment with antidiarrheal compounds and fluid and electrolyte replacement to alleviate the dehydration accompanying diarrheal illness.
None of these aforementioned references and publications, however, is believed to disclose or suggest the use of Syringomycin-family lipodepsipeptides as a method of/for controlling or preventing infections caused by protozoans. From the foregoing, it would be advantageous to provide methods for combating and preventing protozoal infections in mammals.